Topotecan in Treating Patients With Myelodysplastic Syndrome

A Randomized Phase II Trial of Oral Topotecan Given Twice a Day for 5 Days or Once a Day for 10 Days to Patients With Myelodysplastic Syndromes (MDS)

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die.

PURPOSE: Randomized phase II trial to study the effectiveness of topotecan in treating patients who have myelodysplastic syndrome.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes; Leukemia
• Intervention / Treatment: Drug: topotecan hydrochloride

Detailed Description

OBJECTIVES: I. Estimate complete or partial remission, hematologic improvement, and cytogenic response rate when oral topotecan is given twice a day for 5 days versus once a day for 10 days to patients with myelodysplastic syndromes. II. Evaluate the safety and toxicity of oral topotecan in these patients. III. Evaluate whether there are morphologic and/or cytogenetic subsets of the myelodysplastic syndromes that will respond optimally to this regimen. IV. Evaluate the change in the percentage of bone marrow blast cells in these patients during treatment. V. Evaluate the time to transformation to acute myeloid leukemia (AML) or death in this patient population.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to FAB subtype: 1. Refractory anemia with excess blasts 2. Refractory anemia with excess blasts in transformation 3. Chronic myelomonocytic leukemia 4. Refractory anemia, refractory anemia with ringed sideroblasts, and refractory cytopenia with multilineage dysplasia Patients are randomized to receive oral topotecan either twice daily for 5 days or once daily for 10 days. Courses are repeated every 21 days. Patients are evaluated for hematologic response after the initial 2 courses, and then every 4 courses. If a partial response or hematologic improvement is observed, treatment continues until disease progression to acute myeloid leukemia, relapse, death, or irreversible toxicity. Patients who achieve a complete response receive an additional 2 courses of therapy before discontinuation of protocol treatment. Patients are followed every 3 months for 2 years, then every year for an additional 3 years, and at time of progression.

PROJECTED ACCRUAL: A total of 90 patients (45 per arm) will be accrued for this study within 13 months.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Veterans Affairs Medical Center - Birmingham
  • California
    • La Jolla, California, United States, 92093-0658
      • University of California San Diego Cancer Center
    • San Francisco, California, United States, 94121
      • Veterans Affairs Medical Center - San Francisco
    • San Francisco, California, United States, 94115-0128
      • UCSF Cancer Center and Cancer Research Institute
  • Delaware
    • Wilmington, Delaware, United States, 19899
      • CCOP - Christiana Care Health Services
  • District of Columbia
    • Washington, District of Columbia, United States, 20307-5000
      • Walter Reed Army Medical Center
    • Washington, District of Columbia, United States, 20007
      • Vincent T. Lombardi Cancer Research Center, Georgetown University
  • Florida
    • Miami Beach, Florida, United States, 33140
      • CCOP - Mount Sinai Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Veterans Affairs Medical Center - Chicago (Westside Hospital)
    • Chicago, Illinois, United States, 60640
      • Louis A. Weiss Memorial Hospital
    • Chicago, Illinois, United States, 60637
      • University of Chicago Cancer Research Center
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago Health Sciences Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University Of Iowa Hospitals And Clinics
  • Maine
    • Togus, Maine, United States, 04330
      • Veterans Affairs Medical Center - Togus
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Marlene & Stewart Greenebaum Cancer Center, University of Maryland
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Memorial Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55417
      • Veterans Affairs Medical Center - Minneapolis
  • Missouri
    • Columbia, Missouri, United States, 65201
      • Veterans Affairs Medical Center - Columbia (Truman Memorial)
    • Columbia, Missouri, United States, 65203
      • Ellis Fischel Cancer Center - Columbia
    • Saint Louis, Missouri, United States, 63110
      • Barnes-Jewish Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68198-3330
      • University of Nebraska Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • CCOP - Southern Nevada Cancer Research Foundation
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Norris Cotton Cancer Center
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute
    • Buffalo, New York, United States, 14215
      • Veterans Affairs Medical Center - Buffalo
    • Manhasset, New York, United States, 11030
      • CCOP - North Shore University Hospital
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
    • New York, New York, United States, 10021
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10021
      • New York Presbyterian Hospital - Cornell Campus
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center, NY
    • Syracuse, New York, United States, 13210
      • State University of New York - Upstate Medical University
    • Syracuse, New York, United States, 13210
      • Veterans Affairs Medical Center - Syracuse
    • Syracuse, New York, United States, 13210
      • CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Lineberger Comprehensive Cancer Center, UNC
    • Durham, North Carolina, United States, 27705
      • Veterans Affairs Medical Center - Durham
    • Durham, North Carolina, United States, 27710
      • Duke Comprehensive Cancer Center
    • Winston-Salem, North Carolina, United States, 27104-4241
      • CCOP - Southeast Cancer Control Consortium
    • Winston-Salem, North Carolina, United States, 27157-1082
      • Comprehensive Cancer Center of Wake Forest University Baptist Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Arthur G. James Cancer Hospital - Ohio State University
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425-0721
      • Medical University of South Carolina
  • Tennessee
    • Memphis, Tennessee, United States, 38104
      • Veterans Affairs Medical Center - Memphis
    • Memphis, Tennessee, United States, 38163
      • University of Tennessee, Memphis Cancer Center
  • Vermont
    • Burlington, Vermont, United States, 05401-3498
      • Vermont Cancer Center
    • White River Junction, Vermont, United States, 05009
      • Veterans Affairs Medical Center - White River Junction
  • Virginia
    • Richmond, Virginia, United States, 23298-0037
      • MBCCOP - Massey Cancer Center
    • Richmond, Virginia, United States, 23249
      • Veterans Affairs Medical Center - Richmond

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 120 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS: Primary or therapy-related myelodysplastic syndrome: Refractory anemia with excess blasts Refractory anemia with excess blasts in transformation Chronic myelomonocytic leukemia Refractory anemia, refractory anemia with ringed sideroblasts, or refractory cytopenia with multilineage dysplasia These patients must also have one of the following criteria: Greater than 4 units of RBCs transfused within the past 3 months OR Platelet count less than 50,000/mm3 OR Neutrophil count less than 1,000/mm3 AND a recent infection requiring antibiotics

PATIENT CHARACTERISTICS: Age: Over 15 Performance status: 0-2 Life expectancy: Not specified Hematopoietic: See Disease Characteristics Hepatic: Bilirubin no greater than 1.5 mg/dL SGOT no greater than 2 times upper limit of normal Renal: Creatinine no greater than 1.5 mg/dL Other: Not pregnant or nursing Fertile patients must use effective contraception Free of any evidence of prior cancer for at least 12 months

PRIOR CONCURRENT THERAPY: Biologic therapy: At least 1 month since prior interferon No prior hematopoietic growth factors or cytokines except epoetin alfa No concurrent epoetin alfa Chemotherapy: No prior topotecan No prior chemotherapy for this disease At least 12 months since prior chemotherapy for another disease No other concurrent chemotherapy Endocrine therapy: At least 1 month since prior corticosteroids No concurrent hormonal therapy for disease-related conditions Concurrent steroids for adrenal failure allowed No concurrent dexamethasone and other steroidal antiemetics Radiotherapy: No prior radiotherapy for this disease At least 12 months since prior radiotherapy for another disease Surgery: Not specified Other: No prior cytotoxic therapy (including low-dose antimetabolites) for this disease At least 1 month since prior retinoids

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oral Topotecan 5 days; Patients receive intervention twice daily for 5 days	Drug: topotecan hydrochloride; 1.2 mg/sq m twice a day for 5 days (Arm I) and once a day for 10 days (Arm II)
Experimental: Oral Topotecan 10 days; Patients receive intervention once daily for 10 days	Drug: topotecan hydrochloride; 1.2 mg/sq m twice a day for 5 days (Arm I) and once a day for 10 days (Arm II)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response	Response in the peripheral blood is assessed during tx, q 3 mon for 2 yrs post tx, then annually for another 3 years, and then at progression Bone marrow response is assessed prior to cycle 3, then q 4 cycles for the 1st yr. then q 8 cycles for patients who continue beyond	During treatment and up to progression post treatment
Toxicity	assessment during treatment, q 3 mon for 2 years post tx, then annually for another 3 yrs, then at progression	during treatment until progression

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: David L. Grinblatt, MD, Louis A. Weiss Memorial Hospital

Publications and helpful links

General Publications

• Klein CE, Kastrissios H, Miller AA, Hollis D, Yu D, Rosner GL, Grinblatt DL, Larson RA, Ratain MJ. Pharmacokinetics, pharmacodynamics and adherence to oral topotecan in myelodysplastic syndromes: a Cancer and Leukemia Group B study. Cancer Chemother Pharmacol. 2006 Jan;57(2):199-206. doi: 10.1007/s00280-005-0023-6. Epub 2005 Sep 13.
• Grinblatt DL, Yu D, Hars V, et al.: Relationships of response to oral topotecan (Topo) for myelodysplastic syndrome (MDS) with IPSS group and cytogenetics - CALGB study 19803. [Abstract] Blood 100 (11 Pt 1): A-3137, 2002.
• Grinblatt DL, Yu D, Klein C, et al.: Two schedules of oral topotecan for myelodysplastic syndrome (MDS)-CALGB study 19803. [Abstract] Proceedings of the American Society of Clinical Oncology 20: A-1209, 2001.

Study record dates

Study Major Dates

• Study Start: March 1, 1999
• Primary Completion (Actual): January 1, 2002
• Study Completion (Actual): April 1, 2009

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: July 21, 2004
• First Posted (Estimate): July 22, 2004

Study Record Updates

• Last Update Posted (Estimate): July 20, 2016
• Last Update Submitted That Met QC Criteria: July 19, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: refractory anemia; refractory anemia with ringed sideroblasts; refractory anemia with excess blasts; refractory anemia with excess blasts in transformation; chronic myelomonocytic leukemia; de novo myelodysplastic syndromes; secondary myelodysplastic syndromes; childhood myelodysplastic syndromes; refractory cytopenia with multilineage dysplasia
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Topotecan
• Other Study ID Numbers: CALGB-19803; U10CA031946 (U.S. NIH Grant/Contract); CLB-19803; CDR0000066776 (Registry Identifier: NCI Physician Data Query)